Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed against Prostate Cancer
Abstract
Approximately 30,000 men in the United States died of prostate cancer in 2013 with a similar estimate for 2014, making this disease the second most common cause of cancer-related death among men. White blood cells normally play a vital role in preventing tumor growth; however, the microenvironment associated with prostate cancer is able to turn off the immune system, allowing these tumors to become malignant. Reports indicate that a specialized host cell, termed a regulatory T cell (Treg), undermines immune responses directed against prostate cancer to the extent that elimination of these Tregs promotes tumor clearance. Unfortunately, Tregs are necessary to prevent lethal autoimmunity, which precludes Treg elimination as a form of cancer therapy. Instead, treatments are required that limit Treg-mediated activity directed towards prostate cancer without affecting self-tolerance. Recently, we have discovered that the molecule Kruppel-like factor 2 (KLF2) is necessary for the generation of Tregs that repress tumor-specific immune responses. Importantly, elimination of these KLF2-dependent Tregs does not contribute to autoimmunity, which suggests that purging these cells is a safe means of treating prostate cancer. Therefore, the current research proposal is predicated on the hypothesis that KLF2-dependent Tregs are responsible for shutting off tumor-specific immune responses. To test this hypothesis, we will take advantage of an established mouse model that spontaneously develops prostate cancer to investigate how elimination or amplification of KLF2-dependent Tregs impacts disease. Initial experiments will determine if prostate cancer is prevented in mice that lack KLF2-dependent Tregs. Follow-up experiments will then investigate if eliminating KLF2-dependent Tregs after animals develop cancer is a viable means of treating prostate cancer. Conversely, accelerated KLF2-dependent Treg production may foster prostate cancer progression, which we will test using mouse models that have increased numbers of these regulatory cells. If our hypothesis is correct, mice that lack KLF2-dependent Tregs will have a lower incidence/less severe form of prostate cancer. Moreover, removal of this Treg lineage will safely restore immune responses directed against prostate cancer, thus proving that this is a practical cancer therapy. On the other hand, mice that have increased numbers of KLF2-dependent Tregs should be more inclined for prostate cancer, both in terms of susceptibility and progression. These latter results are especially relevant since we have discovered that several drugs, including cholesterol-lowering statins that are prescribed to one-quarter of all Americans over the age of 45, promote the generation of KLF2-dependent Tregs. Results derived from this grant proposal will have a broad impact on several fields, ranging from basic immunological research that strives to understand how self-tolerance is maintained in healthy individuals, to the clinical setting where new therapies are desperately needed to treat malignant prostate cancer and associated metastases. Verification of our central hypothesis that KLF2-dependent Tregs promote prostate cancer will identify a viable target for treating this disease at all stages of development. For example, pre-emptive elimination of KLF2-dependent Tregs could prevent prostate cancer onset whereas removal of this Treg subset in patients with late-stage cancer and metastases could potential reverse disease progression. On this note, the primary biologic therapy currently approved to treat prostate cancer is Sipuleucel-T, a multi-step regimen that boosts host immune responses against tumors. Unfortunately, this therapy only extends patients lives an average of 4 months, in part due to the ability of these tumors to quickly re-establish an immunosuppressive environment. However, if one were to eliminate KLF2-dependent Tregs while applying Sipuleucel-T, it is likely that this
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510328
Entities
People
- Eric Sebzda
Organizations
- United States Army
- Vanderbilt University